Survival prospects after acute myocardial infarction in the uk a matched cohort study 1987 2011

Outcome measures:The hazard of all-cause mortality associated with AMI was calculated by a multilevel Cox ’s proportional hazards regression, adjusted for sex, year of birth, socioeconom

Survival prospects after acute myocardial infarction in the UK:

a matched cohort study 1987–2011

Lisanne A Gitsels,1Elena Kulinskaya,1Nicholas Steel2

To cite: Gitsels LA,

Kulinskaya E, Steel N.

Survival prospects after acute

myocardial infarction in the

UK: a matched cohort study

1987 –2011 BMJ Open

2017;7:e013570.

doi:10.1136/bmjopen-2016-013570

▸ Prepublication history and

additional material is

available To view please visit

the journal (http://dx.doi.org/

10.1136/bmjopen-2016-013570).

Received 21 July 2016

Revised 16 December 2016

Accepted 21 December 2016

1 School of Computing

Sciences, University of East

Anglia, Norwich Research

Park, Norwich, UK

2 Norwich Medical School,

University of East Anglia,

Norwich Research Park,

Norwich, UK

Correspondence to

Lisanne A Gitsels;

l.gitsels@uea.ac.uk

ABSTRACT

Objectives:Estimate survival after acute myocardial infarction (AMI) in the general population aged 60 and over and the effect of recommended treatments.

Design:Cohort study in the UK with routinely collected data between January 1987 and March 2011.

Setting:310 general practices that contributed to The Health Improvement Network (THIN) database.

Participants:4 cohorts who reached the age of 60,

65, 70, or 75 years between 1987 and 2011 included

16 744, 43 528, 73 728, and 76 392 participants, respectively Participants with a history of AMI were matched on sex, year of birth, and general practice to 3 controls each.

Outcome measures:The hazard of all-cause mortality associated with AMI was calculated by a multilevel Cox ’s proportional hazards regression, adjusted for sex, year of birth, socioeconomic status, angina, heart failure, other cardiovascular conditions, chronic kidney disease, diabetes, hypertension, hypercholesterolaemia, alcohol consumption, body mass index, smoking status, coronary

revascularisation, prescription of β-blockers, ACE inhibitors, calcium-channel blockers, aspirin, or statins, and general practice.

Results:Compared with no history of AMI by age 60,

65, 70, or 75, having had 1 AMI was associated with

an adjusted hazard of mortality of 1.80 (95% CI 1.60

to 2.02), 1.71 (1.59 to 1.84), 1.50 (1.42 to 1.59), or 1.45 (1.38 to 1.53), respectively, and having had multiple AMIs with a hazard of 1.92 (1.60 to 2.29), 1.87 (1.68 to 2.07), 1.66 (1.53 to 1.80), or 1.63 (1.51

to 1.76), respectively Survival was better after statins (HR range across the 4 cohorts 0.74 –0.81), β-blockers (0.79 –0.85), or coronary revascularisation (in first

5 years) (0.72 –0.80); unchanged after calcium-channel blockers (1.00 –1.07); and worse after aspirin (1.05–

1.10) or ACE inhibitors (1.10 –1.25).

Conclusions:The hazard of death after AMI is less than reported by previous studies, and standard treatments of aspirin or ACE inhibitors prescription may be of little benefit or even cause harm.

INTRODUCTION

Survival after acute myocardial infarction (AMI) has improved over the past decades in

Western countries including the UK both in the short and long term,1–6 partly due to an increase in coronary revascularisation, more effective drug therapy, and healthier life-styles.1–3 6 7 The prevalence of AMI has increased, partly due to the ageing popula-tion, which makes evaluating long-term sur-vival prospects increasingly important for setting out healthcare requirements and resource planning Previous studies have esti-mated mortality rates of AMI standardised for age, sex, deprivation or region2–6 and examined survival variations in AMI patients, usually selected patients through hospitals or registries, by a range of confounders.1 2 5 7–12

A recent population-based cohort study in England with data from 2004 to 2010 con-cluded that after 7 years people with a first

or recurrent AMI had double or triple the risk of mortality compared with the general population of equivalent sex and age.5These hazards are likely to be overestimated, because the study did not include controls and could therefore only compare the results with the sex-standardised and age-standardised mortality rates of the general population AMI patients may be more likely to have comorbidities and an unhealthy lifestyle, which are independent

Strengths and limitations of this study

▪ Large cohort study representative of the full range of patients seen in routine clinical practice

in the UK, which has a better coverage of acute myocardial infarction (AMI) patients than hos-pital records or disease registers.

▪ The matched study design allowed to estimate the effect of a history of AMI on all-cause mor-tality compared with no history of AMI while adjusting for a wide range of confounders.

▪ Although the major confounders of AMI were adjusted for, there could potentially be some residual confounding by indication for the treatments.

Gitsels LA, et al BMJ Open 2017;7:e013570 doi:10.1136/bmjopen-2016-013570 1

predictors of survival, and so adjustment for these

con-founders is important.13–15

There is a need for a study that estimates long-term

survival prospects after AMI, adjusts for important

con-founders, and assesses the impact of treatments on

sur-vival With primary care data, information on

demographics, lifestyle factors, comorbidities, and

treat-ments is available for both cases and controls, thus

allow-ing to estimate the adjusted survival difference between

the two groups Additionally, primary care has a better

coverage of patients with AMI than hospitals and

regis-ters, because it includes patients who were diagnosed

immediately and patients who were not sent to the

hos-pital but were diagnosed in routine practice later by

blood test results.16 Between 2003 and 2009, primary

care covered 75% of the AMI cases in England while

hospital and register data covered 68% and 52%,

respectively.16 The three data sources had similar

preva-lence of risk factors and mortality rates of AMI.16

The objectives of this study were to estimate the

hazard of mortality associated with a history of a single

or multiple AMIs at key ages in UK residents while

con-trolling for a wide range of confounders, and to estimate

how survival prospects of AMI patients were changed by

coronary revascularisation and recommended drug

therapy

METHODS

Study design

This matched cohort study made use of medical records

from The Health Improvement Network (THIN)

data-base These records are representative of the UK

popula-tion regarding demographics, prevalence of medical

conditions, and mortality rates when adjusted for

deprivation.17 18

Four cohorts of patients who were born between 1920

and 1940 and turned the initial age in 1987–2011 were

selected The initial ages were 60, 65, 70, and 75, chosen

to provide advice on future management plans and

resource planning at key ages.14 The selected patients

had to be registered for at least 1 year at a general

prac-tice that coded death dates validly The patient’s record

had to include a postcode and should have been

accessed at least once within the past 10 years From

these cohorts, patients with a history of AMI were

selected and each was matched to three controls without

history on sex, year of birth category, and general

prac-tice The study’s end date was the 18th of March 2011,

thus patients were followed-up for up to 24 years

Patients could be part of multiple cohorts Patients who

changed general practice during the study could no

longer be observed It was assumed that the loss to

follow-up was not associated with the outcome mortality

Patient involvement

No patient was involved in setting the research question,

outcome measures, design or conduct of the study The

results were not disseminated to the patients, as the study was based on anonymised patient records

Variable selection

The baseline characteristics of patients were assessed on the 1st of January of the year they turned the cohort’s age The primary exposure was AMI Multiple events were required to be separated by 30 days Information

on the type of AMI was not available However, a study that linked information from the Myocardial Ischaemia National Audit Project (MINAP) and the General Practice Research Database (GPRD), which has 60% of practices in overlap with THIN, found that 46% of AMIs were ST-elevated (ST segment elevation myocardial infarctions, STEMIs) in England and Wales in

2003–2008.19 The selected confounders were based on literature review, and consisted of: sex, year of birth, socioeconomic status, angina pectoris, heart failure, other cardiovascular conditions (valvular heart disease, peripheral vascular disease, and cerebrovascular disease), chronic kidney disease, diabetes mellitus, hypertension, hypercholesterolaemia, alcohol consump-tion, body mass index (BMI), and smoking status (see online supplementary tables SA1 and SA2) Socioeconomic status was measured by Mosaic, which is based on demographics, lifestyles, and behaviour of people at a postcode level.20

The treatment investigated was based on the UK National Institute of Health and Care Excellence (NICE) recommended first-line treatment to AMI patients during the study period, which includes: coron-ary revascularisation and prescription of ACE inhibitors, aspirin, β-blockers, calcium-channel blockers, and statins.21–23 Since 2007, calcium-channel blockers are only recommended to treat hypertension or angina in AMI patients.22 23 Since 2013, dual antiplatelet therapy (DAPT: aspirin plus another antiplatelet agent) are rec-ommend to AMI patients.22 23 Owing to the low preva-lence of DAPT in the age cohorts, the survival effect of the therapy were not estimated (see online supplementary table SA3) Family history of AMI or car-diovascular disease were not included in the analysis because of the very low rates of recording in primary care.24 Indicators of psychosocial factors such as job strain and lack of social support, fruit and vegetable intake, and physical activity were not included in the analysis because THIN does not hold information on them

There were missing values in alcohol consumption ( proportion range across the four cohorts 17–37%), BMI (18–37%), and smoking status (10–29%) The frac-tion of incomplete medical records decreased with age; 45% of the youngest cohort and 23% of the oldest cohort had incomplete records Incomplete records were more common in patients born at an earlier year and in patients without medical conditions or on treat-ments (see online supplementary table SA4) This is in accordance with previous research that reported that

recording has improved since the introduction of

Quality and Outcomes Framework (QOF) in 2004.25–27

Missing values were dealt with by multiple imputation.28

The distribution of known and imputed values were

similar (see online supplementary table SA5)

Statistical analyses

A Cox’s proportional hazards regression model was

fitted to estimate the effect of a history of AMI and

respective treatments on the hazard of all-cause

mortal-ity at different ages The outcome variable was time to

death in days, that is, from 1st of January of the year the

patient turned the cohort’s age to the date of death

Starting from a model with second-order interaction

effects of all variables with the main exposure AMI and

the matching factors sex and year of birth, backward

elimination was performed to obtain the most

parsimo-nious model possible Interaction effects found in the

complete case analysis, that is, the analysis that excluded

patients with incomplete medical records, which were

not restricted to the main exposure and matching

factors, were also included in the backward elimination

process A unified model for all ages was chosen to have

the same interpretation of the hazards

The final model included sex, year of birth,

socioeconomic status, AMI, angina, heart failure, other

cardiovascular conditions, chronic kidney disease,

dia-betes, hypertension, hypercholesterolaemia, coronary

revascularisation, β-blockers, ACE inhibitors,

calcium-channel blockers, aspirin, statins, alcohol consumption,

BMI, smoking status, general practice, and interactions

of AMI with angina, AMI with β-blockers, AMI with calcium-channel blockers, hypercholesterolaemia with statins, and BMI with smoking status Chronic kidney disease was not adjusted for at ages 60 and 65 due to low prevalence of <1%

The number of years gained or lost due to a history of AMI, coronary revascularisation, and drug therapy were calculated.29The models were assessed on validity of pro-portional hazards assumption, overall performance, dis-crimination, and external validation.30–32 The sensitivity analysis compared the unadjusted and adjusted effect of

a history of AMI estimated on the imputed datasets For more detailed information on the statistical ana-lyses, please see online supplementary data

RESULTS

The prevalence of comorbidities was higher among AMI cases than controls (figure 1 and table 1) Obesity (BMI≥30 kg/m2) was more common among cases, whereas overweight (BMI 25–30 kg/m2) was as common among cases as controls The prevalence of smokers was the same in the two groups, while the prevalence of ex-smokers was greater among cases

Prevalence of treatment

The prevalence of coronary revascularisation and drug therapy was higher among patients who had multiple AMIs compared with patients who had a single AMI (table 2) The rates across the four age cohorts for

Figure 1 Selection of cohorts AMI, acute myocardial infarction.

Gitsels LA, et al BMJ Open 2017;7:e013570 doi:10.1136/bmjopen-2016-013570 3

Open Access

Table 1 Characteristics of acute myocardial infarction (AMI) cases and controls by age cohort

Total person-years of follow-up (mean) 46 686 (11.2) 150 471 (12.0) 93 056 (8.6) 299 841 (9.2) 114 700 (6.2) 370 006 (6.7) 91 884 (4.8) 298 140 (5.2) Deaths during follow-up (%) 1220 (29%) 2008 (16%) 3070 (28%) 5782 (18%) 5186 (28%) 10 557 (19%) 5895 (31%) 12 674 (22%) Transferred during follow-up (%) 900 (22%) 3035 (24%) 1986 (18%) 6597 (20%) 2693 (15%) 8781 (16%) 2733 (14%) 8971 (16%) Male (%) 3367 (80%) 10 101 (80%) 8402 (77%) 25 206 (77%) 13 567 (74%) 40 701 (74%) 13 163 (69%) 39 489 (69%)

Other cardiovascular conditions (%) 979 (23%) 681 (5%) 3154 (29%) 2941 (9%) 6591 (36%) 7672 (14%) 8205 (43%) 11 674 (20%)

Hypercholesterolaemia (%) 1634 (39%) 1907 (15%) 4228 (39%) 7423 (23%) 6392 (35%) 14 936 (27%) 6395 (33%) 15 814 (28%) Hypertension (%) 1168 (28%) 1991 (16%) 3750 (34%) 7608 (23%) 7411 (40%) 17 955 (32%) 8579 (45%) 22 330 (39%) Alcohol consumer (%) ‡ 3385 (81%) 10 997 (88%) 8780 (81%) 28 130 (86%) 14 494 (79%) 45 962 (83%) 14 293 (75%) 45 504 (79%) Overweight (%) ‡ 2427 (58%) 7239 (58%) 5866 (54%) 17 609 (54%) 9406 (51%) 28 253 (51%) 9264 (49%) 28 030 (49%)

Ex-smoker (%) ‡ 1274 (30%) 2398 (19%) 4611 (42%) 10 903 (33%) 8335 (45%) 19 305 (35%) 8695 (46%) 20 641 (36%) Smoker (%) ‡ 1163 (28%) 3507 (28%) 2203 (20%) 6544 (20%) 3079 (17%) 8973 (16%) 2545 (13%) 7660 (13%)

*Participants with a history of AMI.

†Participants with no history of AMI.

‡Mean 10 imputed datasets.

coronary artery bypass graft (CABG) and percutaneous

coronary intervention (PCI) were 16–19% and 3–8%,

respectively (see online supplementary table SA6) Men

were approximately twice as likely to have had coronary

revascularisation as women were, which could not be

explained by age, deprivation, or diabetes (see online

supplementary figure SA1 and table SA7) Men and

women were equally likely to be prescribed drugs From

1995 to 2011, the prevalence of coronary

revascularisa-tion and drug therapy increased substantially, with the

exception of prescription of calcium-channel blockers

which decreased over the years (see online

supplementaryfigure SA2) The difference in treatment

prevalence by the four initial ages converged over time

In 2010 the most widely prescribed drugs to AMI

patients were statins (94%) and aspirin (94%) followed

by ACE inhibitors (85%), β-blockers (65%), and

calcium-channel blockers (25%) In the same year, 38%

of the AMI patients have had coronary revascularisation

by an initial age; the prevalence was greater in patients

living in the most affluent areas (index of multiple

deprivation (IMD) category 1: 45%) than in patients

living in the most deprived areas (IMD category 5:

32%), trendχ2

(1)=5.06, p=0.02

Survival prospects after AMI

The adjusted hazard of all-cause mortality for AMI

patients was constant during follow-up of 24 years; it did

not matter how many years the cases had already sur-vived, they were still at a higher risk of dying than the controls This relative risk was the greatest in the young-est cohort while the absolute risk was the greatyoung-est in the oldest cohort (figure 2 and see online supplementary figure SA3) Compared with no history of AMI by age

60, 65, 70, or 75, having had one AMI was associated with an adjusted hazard of mortality of 1.8 (1.6 to 2.0), 1.7 (1.6 to 1.8), 1.5 (1.4 to 1.6), or 1.5 (1.4 to 1.5), respectively This translates to a decrease in life expect-ancy of 5.9 (4.7 to 7.0), 5.4 (4.6 to 6.1), 4.1 (3.5 to 4.6), and 3.7 (3.2 to 4.3) years, respectively Compared with

no history of AMI by age 60, 65, 70, or 75, having had multiple AMIs was associated with an adjusted hazard of mortality of 1.9 (1.6 to 2.3), 1.9 (1.7 to 2.0), 1.66 (1.5 to 1.8), or 1.6 (1.5 to 1.8), respectively This translates to a decrease in life expectancy of 6.5 (4.7 to 8.3), 6.2 (5.2 to 7.3), 5.1 (4.3 to 5.9), or 4.9 (4.1 to 5.6) years, respect-ively The hazard of mortality did not differ between cases with or without a history of angina There were also interactions with prescriptions of β-blockers and calcium-channel blockers, which are described below There were no other interactions with a history of AMI, meaning that the effect of AMI on the hazard of mortal-ity was the same for different groups of patients, such as for men and women The comorbidities that had the greatest impact on survival were other cardiovascular conditions and heart failure (see online supplementary

Table 2 Baseline treatment given a possible history of IHD

Coronary revascularisation Drug therapy

Single AMI 3465 486 (18%) 77 (11%) 1467 (42%) 768 (22%) 1482 (43%) 951 (27%) 1080 (31%) Multiple

AMIs

Single AMI 8796 1532 (23%) 334 (16%) 5751 (65%) 3452 (39%) 4011 (46%) 4722 (54%) 2762 (31%) Multiple

AMIs

2086 594 (35%) 67 (17%) 1532 (73%) 1072 (51%) 946 (45%) 1272 (61%) 722 (35%)

Angina 5528 1263 (28%) 125 (12%) 3851 (70%) 2204 (40%) 2376 (43%) 3335 (60%) 2235 (40%) Single AMI 14 847 2811 (26%) 730 (18%) 11 269 (76%) 7770 (52%) 6989 (47%) 9638 (65%) 4461 (30%) Multiple

AMIs

3585 1012 (36%) 172 (22%) 2918 (81%) 2202 (61%) 1721 (48%) 2524 (70%) 1219 (34%) Age 75 No 49 822 0 (0%) 0 (0%) 12 592 (25%) 12 633 (25%) 7945 (16%) 11 318 (23%) 8574 (17%)

Angina 7472 1652 (29%) 225 (13%) 5642 (76%) 3430 (46%) 3188 (43%) 4780 (64%) 2952 (40%) Single AMI 15 319 2705 (26%) 835 (17%) 12 487 (82%) 9226 (60%) 7036 (46%) 10 395 (68%) 4676 (31%) Multiple

AMIs

3779 954 (35%) 230 (23%) 3295 (87%) 2574 (68%) 1759 (47%) 2767 (73%) 1228 (32%)

*The age cohorts included cases with history of AMI who were matched to three controls on sex, year of birth category, and general practice The prevalence of treatment by the initial ages was affected by calendar year (see online supplementary figure SA2).

†First-line drugs prescription until 2007 after which it became a second-line drugs prescription 2

AMI, acute myocardial infarction; IHD, ischaemic heart disease.

Gitsels LA, et al BMJ Open 2017;7:e013570 doi:10.1136/bmjopen-2016-013570 5

Open Access

figures SA4–7) The associated impact was greatest in

the youngest age cohort On average the comorbidities

led to an additional decrease in life expectancy of 4.6–

7.1 years

Coronary revascularisation was associated with a

sig-nificant improvement in the survival prospects in the

short-term (figure 3) Compared with no history of

cor-onary revascularisation by age 60, 65, 70, or 75, having

had revascularisation was associated with an adjusted

hazard of mortality of 0.8 (0.6 to 1.1), 0.7 (0.6 to 0.8),

0.7 (0.7 to 0.8), and 0.8 (0.7 to 0.8), respectively, in the

first 5 years of follow-up This translates to an increase in

life expectancy of 2.3 (−0.5 to 5.0), 3.3 (2.0 to 4.7), 3.1

(2.2 to 4.0), and 2.5 (1.7 to 3.2) years, respectively After

5 years of follow-up, a history of coronary

revascularisa-tion was no longer associated with a significant

improve-ment in the survival prospects These prospects were the

same for men and women

Drug therapy was associated with mixed survival

prospects and could differ by subgroups of patients

(figure 3) The drug therapy that was associated with

the greatest improved survival prospects was prescription

of statins; the prescription translated to an average

increase in life expectancy of 2.5 years at all ages The

hazard of mortality associated with statins prescription

did not differ between patients with or without a history

of hypercholesterolaemia Prescription ofβ-blockers was

associated with mixed survival prospects; prescription

translated to an average increase in life expectancy of

2.0 years at all ages in AMI patients versus no increase in

patients without AMI Prescription of calcium-channel

blockers was also associated with mixed survival

pro-spects; prescription translated to no increase in life

expectancy in AMI patients versus an average decrease

in life expectancy of 2.0 years in patients without AMI

Prescription of aspirin or ACE inhibitors was associated

with worsened survival prospects; the prescription trans-lated to an average decrease in life expectancy of 1.0 and 1.5 years, respectively, at all ages There were no

sig-nificant differences in the effects of the treatments by sex

Survival prospects differed by socioeconomic status, in which the difference was greater at a younger age The Mosaic category 5 (‘neighbourhood with mainly young couples’) was associated with the worst survival prospects for patients aged 60 and older, this ranged from an adjusted hazard of mortality of 1.7 (1.4 to 2.1) at age 60

to 1.3 (1.2 to 1.4) at age 75 (see online supplementary figures SA3–6) In addition, survival prospects varied considerably between general practices The 95% toler-ance interval of the adjusted hazard of mortality asso-ciated with general practice was 0.8 to 1.2 at age 60 and 0.6 to 1.5 at older age This translates to an average of 4.5 and 10.0 years difference in life expectancy, respect-ively A general practice could serve a range of patients with regards to health status, ethnic background, depriv-ation, urbanisation, and pollution These factors, however, did not explain the hazard of mortality asso-ciated with general practice (see online supplementary methods and table SA8)

Model performance

Please see the online supplementary data for model per-formance and sensitivity analysis

DISCUSSION

This matched cohort study estimated the adjusted hazard of all-cause mortality associated with a history of AMI and respective treatments by age 60, 65, 70, or 75

in UK residents using medical records from primary care between 1987 and 2011 In accordance with the

Figure 2 Unadjusted and adjusted effects of a history of ischaemic heart disease on the hazard of all-cause mortality *Age cohorts consisted of cases who had a history of acute myocardial infarction (AMI) and controls who had no history of AMI The hazard of mortality associated with single/multiple AMIs includes possible history of angina **Adjusted for sex, year of birth, socioeconomic status, heart failure, other cardiovascular conditions, chronic kidney disease (only at ages 70 and 75), diabetes, hypertension, hypercholesterolaemia, coronary revascularisation, statins, β-blockers, ACE inhibitors, calcium-channel blockers, aspirin, alcohol consumption, body mass index, smoking status, and general practice.

literature, this study found that AMI survivors have a

long term, increased hazard of mortality, in which

younger survivors and survivors of multiple events were

worse off.1 2 5 7–12 However, this study estimated lower

hazards of mortality than previously estimated Survival

was better in those who had coronary revascularisation

or were prescribed statins or β-blockers, but worse in

those prescribed aspirin or ACE inhibitors, and

unchanged in those prescribed calcium-channel block-ers The estimated hazards of mortality associated with these treatments were almost the same at each age, implying that the effectiveness of treatments does not differ by age

The lower estimated hazards of mortality associated with a history of AMI reported by this study compared with previous studies could be due to the different data

Figure 3 Adjusted effects of a

history of treatment on the hazard

of all-cause mortality.

*Time-varying effect of a history

of coronary revascularisation on

the hazard of mortality was split

at 5 years of FU after the initial

age **Adjusted for sex, year of

birth, socioeconomic status, AMI,

angina, heart failure, other

cardiovascular conditions, chronic

kidney disease (only at ages 70

and 75), diabetes, hypertension,

hypercholesterolaemia, alcohol

consumption, body mass index,

smoking status, general practice,

and listed treatments Results of

β-blockers and calcium-channel

blockers are reported separately

for cases and controls, because

there was an interaction effect.

AMI, acute myocardial infarction;

Ca-channel, calcium-channel;

FU, follow-up; revasc.,

revascularisation; yrs, years.

Gitsels LA, et al BMJ Open 2017;7:e013570 doi:10.1136/bmjopen-2016-013570 7

Open Access

source used and the range of confounders adjusted for.

This study made use of primary care data, whereas most

studies used hospital and register data Research showed

that the 1-year mortality rate of AMI is lower in primary

care probably because of a lower proportion of severe

cases.16 Furthermore, this study adjusted for a range of

confounders which attenuated the estimated hazards of

mortality associated with a history of AMI There is a

smaller difference between the unadjusted estimates of

this study and the age-standardised and sex-standardised

mortality ratios estimated in English residents based on

hospital and register data from 2004 to 2010 by Smolina

et al.5 It is unlikely that the lower estimated hazards of

mortality reported by this study are due to the shifting

epidemiological trends in cardiovascular disease because

there were no interactions between a history of AMI and

year of birth category or other risk factors with the

exception of angina, β-blockers, and calcium-channel

blockers The medical advances and shifting prevalence

of risk factors over time were adjusted for in the analysis

and had no different survival effects in AMI patients

compared with patients without AMI This study did not

find sex difference in survival prospects after AMI

This is supported by some studies8 10 33 34 but

contra-dicted by another.5 The difference could be explained

by (the lack of ) adjustment for comorbidities and

treatments.8 10 33 34

This study found that the lower uptake of coronary

revascularisation by women could not be explained by

age, diabetes, or deprivation, as suggested by a previous

study.10A study with data from the UK from 2003 to 2008

showed that coronary revascularisation was more

preva-lent in non-STEMIs than in STEMIs.19 As non-STEMIs

are more common among women than among men,19it

seems that type of AMI could not explain the sex

differ-ence in uptake of surgery present in this study In 2012,

the European Society for Cardiology reviewed the sex

dif-ferences in treatment after AMI, taking into account sex

differences in risk profiles, and concluded that sex

differ-ences exist.35 This study also found that a history of

cor-onary revascularisation was no longer associated with a

significantly improved survival prospects after 5 years of

follow-up This is in accordance with another study that

reported a protective effect in the 1-year mortality rate

but an insignificant effect in the 5-year mortality rate of

AMI.10 The findings suggest that coronary

revascularisa-tion might mainly be beneficial in reducing early

mortal-ity No sex difference in survival after coronary

revascularisation was found in this study, which is

sup-ported by some studies5 10but contradicted by another.36

This study found no difference in drugs prescriptions by

sex by 2010, suggesting that the difference converged

over time.3

The findings of this study agree with the clinical

evi-dence reviewed by NICE23 on the effectiveness of statins

and calcium-channel blockers, but disagree with the

effectiveness of ACE inhibitors, aspirin, and β-blockers

The NICE review on ACE inhibitors estimated a

protective effect in AMI patients with left ventricular systolic dysfunction (LVSD) and an inconclusive harmful effect in AMI patients with unselected LVSD in

1986–1993.37–41 Other studies not yet reviewed by NICE, estimated hazardous effects associated with ACE inhibitors and suggested that the results could be due to confounding by heart failure or indication and use of old data (1984–2005).1 12 42 The current study con-trolled for heart failure, which lowered the HR of ACE inhibitors by∼0.05, and made used of more recent data from 1987 to 2011, thereby suggesting that ACE inhibi-tors might in fact be harmful to survival The NICE review on aspirin only included one study that estimated

an inconclusive protective effect of the drug versus placebo on all-cause mortality.23 That study included men with a recent AMI aged 30–64 in 1972–1974.43 The current study made use of more recent data with longer follow-up of older patients of both sexes Aspirin is asso-ciated with an increased risk of bleeding, where the risk increases with age.23Since the elderly are excluded from most clinical trials, it could be that aspirin might actually

be harmful in the elderly as the findings of the current study suggest Thefindings on β-blockers are in concord-ance with more recent published clinical studies1 11 42 that were not yet reviewed by NICE

Finally, this study found that survival prospects varied greatly across general practices, which was independent from health status, ethnic background, deprivation, urbanisation, and pollution Other studies have not reported survival variations by general practice, although

it was adjusted for in a study by Gerberet al.9That study estimated the effect of neighbourhood and individual socioeconomic status on survival after AMI and sug-gested that higher level measured socioeconomic status might capture residual confounding of unequal hospital resources and social characteristics of an area such as social cohesion and attitudes towards health.9

Study’s strengths and limitations

This study used routinely collected primary care data that were representative of the UK.17 18 The advantage

of using primary care data was that there was more infor-mation on sociodemographic and lifestyle factors avail-able and there was a higher coverage of AMI cases.16 The matched study design allowed to estimate the effect

of a history of AMI on mortality compared with no history of AMI while adjusting for a wide range of con-founders The confounders included comorbidities, treatments, lifestyle choices, and demographics, and interactions between these factors This has not been done before; previous studies were either population-based which has a tendency to overestimate the hazard-ous effect of AMI on survival, or previhazard-ous studies only included AMI cases which meant that only survival varia-tions among AMI survivors could be estimated Estimating the effect of a history of AMI at different ages meant that the results could be used for planning ongoing medical management and planning resources

allocation in the British population Finally, the study

had a long follow-up of almost 25 years

Data on the type of AMI were not available in THIN,

therefore this study could not distinguish between

STEMI and non-STEMI and thus could not provide

spe-cific survival prospects for them Although the major

confounders of AMI were adjusted for, there could

potentially be some residual confounding by a number

of other factors: family history of AMI or cardiovascular

disease, psychosocial factors, fruit and vegetable intake,

and physical activity These factors were not adjusted for

in the survival models due to the unsystematic or no

recording in the medical records AMI severity

indica-tors, such as left ventricular function, were also not

included in the survival models because this information

was only available for the cases and not the controls

Missing data in lifestyle factors were dealt with by

mul-tiple imputations This is a widely accepted method to

deal with bias and imprecision when missing data are

present.28Adherence to drug therapy was unknown and

therefore the survival prospects associated with

prescrip-tion of drug therapy might not accurately reflect the

effect of the drugs themselves on mortality

Furthermore, no dose–response effect could be

esti-mated as the prescribed doses were not included in the

survival models Finally, there might be bias by

indica-tion in which patients receiving treatment were

somehow sicker than those not receiving the treatment,

despite the adjustment for important confounders

Recommendations

Thefindings of this study suggest that surviving an AMI

is associated with a permanent increased hazard of

mor-tality and that coronary revascularisation, statins

pre-scription, and β-blockers prescription can reduce this

hazard This is of clinical importance, because not every

AMI survivor receives these treatments In 2010,

β-blockers were not widely prescribed to AMI survivors;

the survival prospects of 35% of the AMI survivors might

be improved by such a prescription This study suggested

that there were sex and deprivation inequalities in

uptake of coronary revascularisation while all subgroups

benefitted equally from it

This study also found that the prescription of aspirin

and/or ACE inhibitors was associated with an increased

hazard of mortality This might be of potential concern

as the previous explanations for similar findings on the

hazardous effects associated with ACE inhibitors on

sur-vival, such as confounding by heart failure and use of

old data, were addressed by this study By 2010, 94% and

85% of AMI survivors were prescribed aspirin and ACE

inhibitor, respectively Further research is required to

assess the effectiveness of aspirin and ACE inhibitors in

the light of ourfindings that such commonly used

medi-cations may be of little benefit, or even cause harm

Further research is needed to explore the reasons for

the considerable unexplained survival variations

between general practices

Contributors LAG implemented the statistical methods, analysed the data, and wrote the first version of the manuscript EK designed the study, provided guidance on the statistical methods and interpretation of the results, and contributed to the writing of the manuscript NS formulated the research questions, provided guidance on the analysis and implications of results, and contributed substantially to the writing of the final version of the manuscript Funding Access to The Health Improvement Network (THIN) database was funded by the University of East Anglia The work by the first two authors was

in part funded by the Economic and Social Research Council (grant number ES/L011859/1).

Competing interests None declared.

Ethics approval This study was approved by the Scientific Review Committee on the 16th of June 2014 (reference number 14-043).

Provenance and peer review Not commissioned; externally peer reviewed Data sharing statement No additional data are available.

Open Access This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited See: http:// creativecommons.org/licenses/by/4.0/

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